Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. In developed countries, tobacco use is estimated to be the largest single cause of premature death, causing approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. Although many areas of the brain participate, the midbrain dopamine (DA) systems serve a vital role in the acquisition of behaviors that are inappropriately reinforced by psychostimulant drugs, including nicotine. The proposed studies examine the following broad hypothesis: during the progression from casual tobacco (nicotine) use to addiction the DA systems change, contributing to the transition to nicotine abuse. The studies specifically examine the physiological changes in the DA systems that evolve as the nicotine exposure continues through time. The changes within the DA systems often use the mechanisms of synaptic plasticity that normally underlie learning and memory. Thus, an ancillary hypothesis is that nicotine induces synaptic changes of the kind that underlie drug-linked memory. Recent advances indicate that addiction shares many commonalities with the synaptic plasticity normally attributed to learning and memory. Drugs subvert normal memory mechanisms, leading to long-lasting changes in behavior that accrue with the ongoing progression of addiction. Subsequently, environmental cues that elicit memories linked to addictive behaviors motivate cravings and relapse. The three aims examine the physiological changes induced by nicotine exposure that progresses from an acute single administration to a short-term chronic exposure and, finally, to a long-term chronic exposure. In each of the three specific aims, we will use in vivo unit recordings to examine nicotine-influences over DA neuron firing patterns and to examine the relationship between DA neurons and the neighboring circuitry. The firing patterns of the DA neurons measured in vivo will guide detailed studies of nicotine modulation of DA release measured using microdialysis and fast cyclic voltammetry. In addition, for each nicotine exposure we will follow the time-course for nicotine-induced synaptic potentiation of the glutamatergic afferents onto DA neurons of the ventral tegmental area. The time course of the synaptic plasticity suggests a window of vulnerability during which DA signaling is altered by drug-associated memory. Our strategy is to investigate DA signaling in vivo, which preserves the overall intact biological systems. Then, we sacrifice some of the pertinence provided by the in vivo studies to pursue greater experimental control and greater detail using in vitro brain slices. A novel combination of physiological studies applied at multiple levels of neuronal integration will provide complementary data sets that are presently lacking within the field of nicotine addiction. PUBLIC HEALTH RELEVANCE Addiction to nicotine motivates tobacco use, which causes approximately 440,000 deaths and more than $75 billion in direct medical costs annually in the USA. This study will determine the nicotine induced short-term and long-term neuronal changes that underlie nicotine addiction. [unreadable] [unreadable] [unreadable]